title: Way forward in case of a false positive in vitro genotoxicity result for a cosmetic substance?
abstract: The currently used regulatory in vitro mutagenicity/genotoxicity test battery has a high sensitivity for detecting genotoxicants, but it suffers from a large number of irrelevant positive results (i.e. low specificity) thereby imposing the need for additional follow-up by in vitro and/or in vivo genotoxicity tests. This could have a major impact on the cosmetic industry in Europe, seen the imposed animal testing and marketing bans on cosmetics and their ingredients. Afflicted, but safe substances could therefore be lost. Using the example of triclosan, a cosmetic preservative, we describe here the potential applicability of a human toxicogenomics-based in vitro assay as a potential mechanistically based follow-up test for positive in vitro genotoxicity results. Triclosan shows a positive in vitro chromosomal aberration test, but is negative during in vivo follow-up tests. Toxicogenomics analysis unequivocally shows that triclosan is identified as a compound acting through non-DNA reactive mechanisms. This proof-of-principle study illustrates the potential of genome-wide transcriptomics data in combination with in vitro experimentation as a possible weight-of-evidence follow-up approach for de-risking a positive outcome in a standard mutagenicity/genotoxicity battery. As such a substantial number of cosmetic compounds wrongly identified as genotoxicants could be saved for the future.
authors.affiliation: Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Electronic address: tatyana.yordanova.doktorova@vub.ac.be.
authors.forename: Tatyana Y
authors.initials: TY
authors.lastname: Doktorova
authors.forename: Gamze
authors.initials: G
authors.lastname: Ates
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.forename: Tamara
authors.initials: T
authors.lastname: Vanhaecke
authors.forename: Vera
authors.initials: V
authors.lastname: Rogiers
mesh_terms: D000891:Anti-Infective Agents, Local / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000139:chemically induced; D003358:Cosmetics / Q000633:toxicity*; D005189:False Positive Reactions; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D009152:Mutagenicity Tests / Q000379:methods*; D043922:Toxicogenetics / Q000379:methods*; D014260:Triclosan / Q000633:toxicity*
chemical_list: D000891:Anti-Infective Agents, Local; D003358:Cosmetics; D014260:Triclosan
keywords: 12-O-tetradecanoylphorbol-13-acetate; 2-nitrofluorene; 2NF; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; AFB1; Aflatoxin B1; BaP; CA; CND; CYCLO; Cosmetic ingredients; D-mannitol; GTX; HCA; K-Nearest Neighbours; KNN; LOO; Leave One Out; MAN; MN; MPH; MTT test; Mutagenicity/genotoxicity test battery; NC; NGTX; NIF; NNK; PCA; PIPB; SDF; SPB; TOL; TPA; TRI; Toxicogenomics-based in vitro models; Triclosan; WYE; Wy-14643; benzo(a)pyrene; chromosome aberration; clonidine; cyclophosphamide; diclofenac sodium; genotoxic; hierarchical clustering analysis; methapyrilene hydrochloride; micronucleus; nifedipine; non-carcinogen; non-genotoxic; phenobarbital sodium; piperonyl butoxide; principle component analysis; tolbutamide